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Heat Shock Proteins May Be New Approach to DMD Treatment

New research suggests that a potential strategy for treating Duchenne muscular dystrophy (DMD) may be to increase levels of heat shock proteins inside muscle fibers.

Heat shock proteins exist naturally inside cells, where they assist in the folding and unfolding of other proteins. Their levels are increased when cells are exposed to various stresses, such as high temperatures.

Muscle physiologist Gordon Lynch, an MDA research grantee and professor and head of the Department of Physiology at the University of Melbourne in Parkville, Victoria, Australia, coordinated the research team, which published its results online April 4, 2012, in the journal Nature.

The findings support the hypothesis that increasing the level of heat shock proteins, particularly one called HSP72, may be beneficial in DMD.

Excess calcium damages muscles in DMD

The underlying defect in DMD is a lack of the muscle protein dystrophin, normally located near the muscle-fiber membrane, where it helps protect muscle fibers from damage.

MDA research grantee Gordon Lynch (left) and postdoctoral researcher Stefan Gehrig at the University of Melbourne

Without dystrophin, muscle fibers are unusually sensitive to mechanical stress, leading to tears and the entry of excess calcium into the fibers.

Excess calcium activates damaging biochemical cascades, such as those involved in tissue inflammation and degeneration. There is ample evidence that this occurs in and contributes significantly to the disease process in DMD.

The study used two types of research mice, each with a disorder resembling human DMD:

mice that lack dystrophin alone, which are not as severely affected as humans with DMD except in their diaphragm muscles, where a great deal of damage occurs; and

mice missing dystrophin and the muscle protein utrophin, which develop a disease that more closely resembles human DMD, with weak back muscles, spinal curvatures and profound limb muscle weakness.

Mice missing both dystrophin and utrophin apparently have even more fragile muscles than mice missing dytrophin alone, with more calcium-related damage from tears.

HSP72 helps SERCA keep calcium in check

Lynch and colleagues chose to increase HSP72 specifically, because this heat shock protein not only performs the usual stress-protecting roles but specifically interacts with a protein called SERCA, which helps regulate cellular calcium levels. SERCA moves calcium ions from places in the cell where they can cause damage to safe storage areas.

The investigators decided to try an HSP72-elevating drug called BGP-15, developed by a company called N-Gene and currently in trials to treat diabetes.

They found that when dystrophin-deficient mice with a DMD-like disease were treated with BGP-15, the mice showed better structure, strength and function in their severely affected diaphragm muscles than did untreated dystrophin-deficient mice. Other evidence from this set of experiments supports the idea that HSP72 was increased and that it helped SERCA protect muscle fibers from calcium-related damage.

In the mice that were deficient in both dystrophin and utrophin, treatment with BGP-15 resulted in decreased spinal curvatures, healthier-appearing limb and diaphragm muscles, and longer life span compared with no treatment.

New treatment avenue now open for exploration

The researchers say their results suggest that HSP72-elevating treatments, including perhaps BGP-15, could provide a new treatment avenue for DMD, one that could be used alone or in combination with other therapies, such as those that increase dystrophin or utrophin levels.

Multicenter team conducted research

Stefan Gehrig, a postdoctoral researcher working with Gordon Lynch at the University of Melbourne, conducted much of the research, investigating several scientific approaches to increasing the levels of HSP72.

"This work took five years to come to fruition," Lynch said. "MDA has been a strong supporter of my laboratory for the last 12 years, and my current grant actually helped fund Stefan when he finished his Ph.D. and continued working on this research during his early postdoctoral period. MDA deserves recognition for contributing to the funding of this work."

Lynch and Gehrig collaborated with Mark Febbraio and his team at Baker IDI Heart & Diabetes Institute in Melbourne, Victoria, Australia; and also with researchers from the University of Oxford, United Kingdom; and Deakin University in Victoria, Australia.